SARS-CoV-2 Infection-Induced Necrotising Sarcoid Granulomatosis

SARS-CoV-2 infection is a pandemic that affects predominantly upper airways and lungs. It may lead to reactivation of known inflammatory rheumatic diseases and/or initiation of various granulomatous disorders. Necrotising sarcoid granulomatosis (NSG) is a rare condition that can be confused with malignancy, granulomatosis with polyangiitis, and sarcoidosis. Herein we reported the development of NSG following a SARS-CoV-2 infection which mimicked granulomatosis with polyangiitis.


INTRODUCTION
Necrotising sarcoid granulomatosis (NSG) is a rare systemic condition characterised by sarcoid-like granulomas, granulomatous vasculitis, and varying degrees of infarct-like necrosis.It was first described in 1973, and it has been unclear since then whether it is a different entity or a spectrum of a known disease such as sarcoidosis or granulomatosis with polyangiitis (GPA). 1,2The most frequent symptoms are cough, fever, dyspnoea, and chest pain.Extra-pulmonary involvement is found in one third of the cases, with ocular being the most common.At imaging, multiple nodules or a solitary mass are found accompanied by mediastinal lymphadenopathy at one third of the cases.It can be clinically mistaken for GPA or malignancy on radiological examination; therefore, biopsy and histopathological evaluation are necessary.SARS CoV-2 infection is a pandemic characterised with upper airway and lung involvement that in some patients may progress to respiratory and multiorgan failure.The clinical manifestations of disease are heterogeneous, which include an asymptomatic carrier, acute respiratory disease (fever, sore throat, cough), and pneumonia of varying degrees of severity.SARS-CoV-2 may lead to reactivation and/ or initiation of various inflammatory rheumatic and granulomatous diseases such as sarcoidosis and/or GPA. 3,4here is no data in the literature yet regarding relationship between SARS-CoV-2 infection and NSG.Herein we reported a 27-year-old male patient who developed SARS-CoV-2-induced NSG.

SARS-COV-2 INFECTION-INDUCED NECROTISING SARCOID GRANULOMATOSIS
Physical examination was unremarkable.The patient works as a translator in our hospital and is at risk for SARS-CoV-2 infection; PCR test was performed and was found positive.The patient was treated only with paracetamol, no additional treatment was required.One month later, the control PCR test was negative, but a lung computed tomography (CT) was planned because he had a dry cough.The patient had a baseline normal lung-X-ray before the infection (Figure 1).Multiple solid nodular lesions in both lungs, with the largest measuring around 3 cm in the right lung middle lobe lateral segment were found on CT scan (Figure 2A).(FDG-PET) -CT was performed; apart from parenchymal nodular lesion in the lungs (standardised uptake value maximum (SUVmax range 2,1-8,1), FDG distribution was normal including hilar-mediastinal lymph nodes (Figure 3).The CT component of the PET confirmed that the paranasal sinuses were also normal.Bronchoscopy was scheduled for the lesion in the middle lobe, bronchoalveolar lavage and bronchoscopic transbronchial punch biopsies were performed.Histopathological findings resulted as chronic inflammation of unknown aetiology and transthoracic fine-needle aspiration biopsy (FNAB) was planned.The two consecutive biopsies resulted as benign cytology.A definitive diagnosis could not be reached after bronchoscopy and fine needle aspiration biopsy (FNAB), and video-assisted thoracoscopic surgery (VATS) biopsy was recommended, and pathology revealed between areas of massive fibrinoid necrosis, histological staining revealed clustered sarcoid granulomas and vasculitic involvement, indicating the diagnosis of NSG (Figure 4).
The patient was treated with 1 mg/kg/day methylprednisolone with isoniazid prophylaxis; the dose of corticosteroid then decreased gradually to 8mg/day.At month three the clinical and radiologic findings have nearly completely disappeared (Figure 2B).Outpatient follow-up of the patient, whose general condition is good, continues.

DISCUSSION
SARS-CoV-2 is an infection characterised with predominantly upper airways and lungs involvement.It is a heterogenous disease which may lead to rapid acute respiratory distress syndrome (ARDS) and pulmonary insufficiency resulting in high morbidity and mortality. 5mmune system dysregulation and possible autoinflammatory and autoimmune mechanisms are responsible for the release of higher amounts of cytokines from immune cells, and severe clinical picture develops as a result of the "perfect cytokine storm". 6As it results, SARS-CoV-2 infection may trigger many inflammatory and autoimmune disorders including granulomatous lung diseases.There are some reports in the literature about the development of granulomatous lung diseases following SARS-CoV-2 infection.Mertz et al. reported three patients with granulomatous manifestations associated with SARS-CoV-2 infection. 7While one of these patients developed sarcoidosis, the other one had activation of established sarcoidosis disease.Capaccione et al. reported the development of sarcoid granuloma after SARS-CoV-2 infection. 8Our recent case is in concordance with those previously reported in the literature.Herein, we report the patient diagnosed with NSG due to SARS-CoV-2 infection which mimics GPA on radiologic evaluation.The patient's radiologic and clinical features start after SARS-CoV-2 infection, and he had no complaints previously.Wide differential diagnoses including GPA, sarcoidosis and malignancy were made and histopathological examination was compatible with NSG (Table 1).

TITLE SARS-COV-2 INFECTION-INDUCED NECROTISING SARCOID GRANULOMATOSIS
The relationship between SARS-CoV-2 infection and development of granulomatous lung diseases are not known yet.One of the hypotheses are the model showing links between SARS-CoV-2 and granulomatous process mechanisms. 9SARS-CoV-2 acts by binding to angiotensin converting enzyme II (ACE II) receptors in 30%-70% of the patients skin, eyes, In 15-20% of active cases; pleura, the central nervous system, the lymphatic system, the genitourinary system, and the bones and joints blood,  13 The authors hypothesise that anti-rheumatic drugs may ameliorate the clinical picture and disease course of COVID-19 in RA patients.The efficacy of various DMARDs with different mechanism of action in the treatment of SARS-CoV-2 infection may explain with the fact that immune system dysregulation and release of higher amounts of cytokines are responsible in its pathogenesis.Targeting the MAIT cells could be an interesting field in both SARS-CoV-2 and granulomatous diseases treatment strategies.More studies in this regard are needed.

CONCLUSION
NSG is a rare disease that can affect anyone at any age and has a wide range of differential diagnoses, the most common of which are malignancy and granulomatosis with polyangiitis.Several triggering factors were reported, and SARS-CoV-2 infection could be one of these.

Figure 2 .
Figure 2. (A) CT scan axial images show multiple parenchymal solid nodules, largest in the right middle lobe.(B) Three months later, control CT images show total regression of the lesions, atelectasis due to the VATS resection.

Figure 2 .
Figure 2. (A) CT scan axial images show multiple parenchymal solid nodules, largest in

Figure 4 .
Figure 4. (A) 4x10 haematoxylin-eosin stain.Peribronchiolar non-necrotising granulomatous inflammation.(B) Prevascular non-necrotising granulomatous inflammation.(C) Necrotising sarcoid granulomatosis.The vessel wall is completely surrounded by granulomatous inflammation.The lumen of the vessel is markedly narrowed (D) Necrotising sarcoid granulomatosis.Lymphocyte and plasma cells can infiltrate arteries and veins.This vein wall is destroyed by the inflammatory infiltrate.

Table 1 .
Comparison between main diseases causing granulomatous inflammation.
12me authors suggest that this MAIT cells might have protective effects from severe or life-threatening infection.These patients have less clinical symptoms and organ involvement.11Recently,theefficacy of various anti-rheumatic drugs in the treatment of SARS-CoV-2 infection were reported.Cherian JJ et al. review the efficacy and safety baricitinib and tocilizumab among hospitalized patients with SARS-CoV-2 infection.12Theyreported that baricitinib and tocilizumab both are recommended interchangeably by various guidelines for the management of SARS-CoV-2 infection considering the mortality data and other comparable efficacy and safety outcomes.Pelechas E et al. reported five patients with RA under treatment with conventional and biological DMARDs which have SARS-CoV-2 infection.